NTR: Term to describe toll ligand proteolytic cascade

[hattrill]

The Toll signaling pathway GO:0008063 is described as "A series of molecular signals initiated by the binding of an extracellular ligand to the receptor Toll on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription."

We would like to have a term to describe the upstream protease cascade (plus its regulation) that leads to the generation of an active ligand (spatzle) for Toll receptors.

• Suggested term label: Either: Toll ligand activation cascade Pro-spatzle activation cascade

• Definition A zymogen activation cascade that leads to the generation of an active protease that cleaves a pro-ligand to an active ligand for the Toll receptor. Starting with the activation of the protease cascade by extracellular recognition factors and ending with the cleave of the Toll receptor pro-ligand (in Drosophila, this ligand is Spatzle).

• Reference

PMID:21209287

• Gene product name and ID to be annotated to this term

• Parent term(s) GO:0072376 protein activation cascade ?(not sure)

• Children terms (if applicable)

• regulation (+ve/-ve) terms as well, please!

tagging @gantonazzo

[ukemi]

I would suggest a child of signaling receptor ligand precursor processing (GO:0140448). I have used its grandchild to annotate the proteases that process EGF-family ligands.

[hattrill]

I would suggest a child of signaling receptor ligand precursor processing (GO:0140448). I have used its grandchild to annotate the proteases that process EGF-family ligands.

Oh, yes. I like that very much!

[raymond91125]

@hattrill what is the source of the figure 2 above? It is not PMID:21209287, I believe. That would be a better reference for below terms.

If I understand it correctly, "Toll signaling pathway" includes TLRs that do not use Spatzle as ligands. How about:

Subclass of GO:0016486 peptide hormone processing "Toll peptide ligand processing" definition "The generation of a mature active peptide ligand for the Toll receptor by the proteolytic cleavage of a pro-ligand to generate a functional ligand. In Drosophila, this ligand is Spatzle."

Subclass of GO:0060568 regulation of peptide hormone processing "regulation of Toll peptide ligand processing" definition "Any process that modulates the frequency, rate or extent of Toll peptide ligand processing."

"positive regulation of Toll peptide ligand processing" definition "Any process that activates or increases the frequency, rate or extent of Toll peptide ligand processing."

"negative regulation of Toll peptide ligand processing" definition "Any process that stops, prevents, or reduces the frequency, rate or extent of Toll peptide ligand processing."

[hattrill]

@hattrill what is the source of the figure 2 above? It is not PMID:21209287, I believe. That would be a better reference for below terms.

@raymond91125 the source for that figure is PMID:23632253

If I understand it correctly, "Toll signaling pathway" includes TLRs that do not use Spatzle as ligands.

Actually, TLRs are covered by GO:0002224 toll-like receptor signaling pathway - the TLR is activated by directly binding pathogen molecules (PAMPs) whereas the Drosophila/insect Toll receptors are activated by processed Spaetzle ligand and are covered by GO:0008063 Toll signaling pathway.

[hattrill]

Thinking about signaling receptor ligand precursor processing/peptide hormone processing, I realise that this won't work for Spatzle as what I want to capture is the cascade of events that final leads to processing of the ligand, whereas "signaling receptor ligand precursor processing" is for the processing steps that act on the ligand itself.

I therefore think that 'protein activation cascade' is more appropriate as the steps are a series of zymogen-activations ending in Spatzle activation by cleavage.

[raymond91125]

I therefore think that 'protein activation cascade' is more appropriate as the steps are a series of zymogen-activations ending in Spatzle activation by cleavage.

I see. How about: "spatzle activation cascade" definition: "A zymogen activation cascade that leads to the generation of an active protease that cleaves an inactive to an active ligand, spazle, for the Toll receptor. Starting with the activation of the protease cascade by extracellular recognition factors and ending with the cleavage of spatzle." PMID:23632253.

Given that there are three parallel cascades, is one term enough for you? You probably don't want to mix the annotations.

But then I don't know if this gets too granular for GO. @pgaudet What do you think?

[pgaudet]

I agree this is very specific, but we have all these other ones:

@hattrill isn't signaling receptor ligand precursor processing sufficient with the ligand as the input?

Thanks, Pascale

[deustp01]

Yet another vignette for the hard uniform-granularity discussion>

[raymond91125]

signaling receptor ligand precursor processing DEF The cleavage of a peptide bond in a precursor form of a signaling receptor ligand, resulting in the mature (active) form of the ligand. That sounds like a single-step process. What @hattrill wants, I believe, is something more like a 'regulation of signaling receptor ligand precursor processing', specifically, the toll ligand spatzle. But the regulation is in itself complex, involving pathways that consists of cascades of proteolytic reactions and their regulations. Thus the proposal of a child of protein activation cascade seems more direct and better.

[pgaudet]

That sounds like a single-step process.

That's right - we should make the definitions more general, as we did for small non-coding RNA processing, which is now "A process leading to the generation of a functional x" (+ including some additions steps as needed).

Wouldn't 'maturation' be more appropriate than 'processing?

Thanks, Pascale

[hattrill]

-One term is enough - I can use annotation extensions to add context for innate immunity, DV patterning. At the moment, the best I can do is give these zymogens +ve regulation of Toll signaling terms, but it is definitely much more than that.

-In terms of maturation - although there is >1 cleavage event for the ligand, it's all done in that final enzyme step, so not quite like ncRNA processing in which end product is derived from a precursor in a series of different ezymatic steps (or even like insulin or EGFR ligand processing). But, if somehow we can shoe-horn a "A process leading to the generation of a functional Toll receptor ligand"; that would be ok for me. I do require a separate "home" for this zymogen cascade/ligand activation pathway, as it has multiple points of regulation and is present in arthopods. I can't think of an equivalent ligand-generation pardigm off-hand, closest I can think of is the complement system.

[raymond91125]

Similar to the term GO:0072378 blood coagulation, fibrin clot formation. a child of protein activation cascade, how about:

"Toll receptor ligand protein activation cascade" definition "A protein activation cascade that contributes to the generation of an active peptide ligand for the Toll receptor and consists of the cascade of enzymatic reactions initiated by by extracellular recognition factors, leading to the cleavage of the inactive form of spatzle." PMID:23632253.

[hattrill]

I like that. It works for me.

[raymond91125]

@hattrill Sorry, I spoke too soon. Do you think it's workable for you to annotate genes involved in the spatzle activation cascade with (new term) signaling receptor ligand activation cascade: A series of modifications to a set of proteins where the product of one reaction catalyzes the following reaction, ultimately leading to the generation of a mature ligand. is_a protein activation cascade (GO:0072376); and specify spatzle as the ligand in annotation extension? We prefer to do it this way because it would avoid specifying a single gene product in the GO term. Thanks for your consideration and patience.

[hattrill]

Hi @raymond91125 I think that this is an exceptional case - can't think of many similarities and as this is a distinguishing feature of arthropod Toll signaling pathways (not TLRs) and there are mulitple enzymes explictly dedicated to this process and many routes, it would get too hard. Spz is at the end, so the individual step would the pro-enzyme as the "has_input" rather thgan spz and then another extension would be needed to say how it was activated e.g. part_of DV axis or innate immune response to X pathogen.

So, would like a special term please!

[pgaudet]

@hattrill does this only occur for the toll ligand? maybe then we dont create the grouping term?

[raymond91125]

The complement system is some what similar https://medium.com/biotechnology-by-tsb/the-complement-system-pathways-and-activation-part-4-antibody-basics-2b28f4db68. "The larger fragment of the complement proteins binds to the target sites and contributes to the activation of other complement proteins in the cascade. At the same time, the smaller fragment of the complement proteins diffuses from the site and can initiate localized inflammatory responses by binding to the specific receptors."

[raymond91125]

I think the question is about whether it's best to create a term addressing Spz specifically (with or without a grouping term) or let Spz be specified some other way (annotation extension or GO-CAM). I'm not experienced in annotation practices. @ukemi @vanaukenk Could you advise? Thanks!

[pgaudet]

WRT the complement system, it seems GO:0006956 complement activation should be given the additional superclass 'protein activation cascade'.

Thanks, Pascale

[addiehl]

It looks like GO:0006956 complement activation already 'has part' some 'protein activation cascade', per AmiGO.

[raymond91125]

good catch @addiehl

[pgaudet]

Wouldn't is_a be more accurate ? I dont see the other parts of complement activation?

[hattrill]

-spz is a family of ligands (one is called Neurotrophin 1 in D.mel):http://flybase.org/reports/FBgg0001052#members so a generic name would be best. -this is the sole job of these zymogens, it's not like a process like the proteasome system. -I think that the alignment with the complement system is very appropriate - it's just a naming thing - both are branched at the point of activation of the pathway and converge via zymogen activation cascades and converge on a point. In the case of complement, the activation of C5 convertase and the assembly of the MAC. In the case of Toll, the result is multiple cleavages of the spz pro-ligand and its dimerization to an active form. Both are innate (toll also has a dev role). So, it comes down to the name: One has a nice grouping name 'the complement system" and not the MAC assembly pathway and the extracellular Toll ligand/spz cascade does not. So, it could be called the spz/spz family activation cascade or the toll ligand activation cascade (with spz synonym), is_a protein activation cascade'.

[raymond91125]

@hattrill Would you be interested in coming to a GO ontology developer meeting (Monday 9AM PST) so that we can discuss this with the larger group in real time? @pgaudet When do you think we can fit Helen in, June 20th?

Again, I'm sorry this takes so much time but it touches on some fundamental issues of GO moving forward.

[hattrill]

June 20th would be fine for me.

[raymond91125]

Summary of alternative proposals

• protein maturation
• • is_a protein activation cascade (GO:0072376)
• • • is_a signaling receptor protein ligand activation cascade

OR

• is_a Toll receptor ligand protein activation cascade

[hattrill]

Thanks @raymond91125!

Could I also have regulation terms (+/-) for this process as well (you might have done this - I might not have interpreted the push req properly)

[raymond91125]

regulation terms added. Thanks for reminding me. @hattrill